SUMMARY Malignant gliomas, the most deadly neurological disease in the brain, are essentially incurable due to their rapid growth and very invasive nature. One paradigm-shifting therapeutic approach to eliminating brain tumors is to change the fate of glioma cells so that they are non-proliferative and non-invasive. We previously showed that virus-mediated expression of two transcription factors directly converts human fibroblasts to neurons with extremely high efficiency. Unexpectedly, our preliminary results also revealed that malignant human glioma cells can be very efficiently converted to neuron-like cells, which are no longer proliferative or invasive. Even the cells that are transduced but not yet fate-converted stopped proliferation, indicating a dominant role for these factors in governing the behavior of human glioma cells. Our preliminary results further show that majority of the in vivo converted cells cannot survive in the adult brain environment. Based on these very exciting findings, we propose to tease out the molecular mechanism underlying forced terminal differentiation of human glioma cells that is mediated by a synergistic action of two transcription factors. We will specifically focus on transcriptome, cistrome, global chromatin structure and epigenetic modifications during the reprogramming process. Results from this study may lead to the identification of nodal points controlling the behavior of human glioma cells, which can be targeted for developing novel therapeutics against the most deadly brain disease-glioblastoma.